Throughout this application various publications are referenced by a number within parentheses. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
Arterial hypertension is a condition of sustained elevated systemic arterial blood pressure. The minimum level of systemic arterial pressure considered to be hypertensive has been arbitrarily set at 140/90 mm Hg. While hypertension usually involves elevations in mean and pulse pressures, the rise in diastolic pressure is clinically regarded as the critical criterion, suggesting that hypertension is due primarily to an increased peripheral resistance.
Hypertension is a serious cardiovascular disease. It is responsible for approximately 10 percent of deaths in people over 50 years of age. However, many of the people in this group may have blood pressures as high as 170/90 without displaying any symptoms of hypertension, and approximately 75 percent of these individuals die of diseases which may have caused their hypertension.
Hypertension is an important clinical disorder because it leads to organic alterations of the heart, brain, kidneys, and arterial vasculature. In hypertension, the heart must pump blood into the arterial systems against a higher than normal level of pressure. Consequently, the heart must perform additional work, and therefore it hypertrophies. Hypertrophy may eventually lead to myocardial failure. The cerebral vasculature does not possess the tissue support found in other regions of the body, and cerebral hemorrhages in hypertensives are not uncommon. Renal insufficiency, which results from arterionephrosclerosis, is a frequent complication of hypertension. The continuous added stress placed upon the arterial system in hypertension ultimately leads to sclerosis of the arterial wall. This alteration of the vascular system may modify tissue blood flow and thereby cause disruption of tissue function.
In approximately 30 percent of the cases of hypertension, the elevated blood pressure is a clinical sign of specific disease, e.g., renal disease, and not a disease entity in itself. Such conditions of elevated blood pressures are referred to as secondar hypertension. In the remaining 70 percent the development of hypertension cannot be attributed to any known origin and probably represents a specific disease state.
Essential hypertension refers to this sustained elevation in systemic arterial blood pressure for which there is no discernible origin. The hypertension may be "benign" in that it may develop slowly and progressively over many years, or it may be "malignant" and develop rapidly in a brief period of time. Attempts to identify the cause of essential hypertension have been fruitless. After exclusion of hypertension due to renal disease, adrenal dysfunction, or cardiovascular and neurogenic alterations, no reasonable explanation is obvious at this time.
The spontaneously hypertensive rat (1) exhibits features observed in human essential hypertension (2-5) and has evoked considerable interest as a model of the human disease. Abnormalities of calcium binding or translocation, for example, have been detected both in the genetically-determined rat disorder (2,6-15) and in the human disease (2,5,16). These calcium abnormalities are of particular significance because they may underlie the pathogenesis of the hypertension (6-12, 14-16).
In spontaneously hypertensive rats (SHR) the alterations include reduced binding of calcium to the plasma membranes of various cell types (2,13-15); impaired flux of calcium out of the cystosol via active transport dependent on adenosine triphosphate (7-12, 14); and increased passive permeability of erythrocyte membranes to the cation (14). These changes are expected to increase the ionized Ca.sup.2+ concentration of the cytosol and in the case of the excitable cells to enhance vascular smooth muscle tone and the peripheral resistance of the blood circulation (15). In human essential hypertension the binding of calcium to erythrocyte membranes is decreased as compared to normotensive controls (2) and the concentration of ionized Ca.sup.2+ within blood platelets is elevated (16).
The foregoing evidence points to a genetically-determined alteration in SHR of a membrane component responsible for binding calcium. The isolation from rat intestinal mucosa of an integral membrane calcium binding protein, IMCAL, which binds calcium with relatively high affinity and is regulated by vitamin D and the level of dietary calcium has been described (17-19). Evidence that the calcium binding activity of intestinal IMCAL is closely correlated with the capacity of the mucosa to transport the cation (17, 20) suggests that IMCAL is a component of the membrane mechanism which mediates or regulates calcium translocation. Immunoassays which utilized polyclonal antisera or a mouse monoclonal antibody to IMCAL have demonstrated that the proteinis present in many rat tissues (19). Because decreases in IMCAL content might account for the reduction in calcium binding to membranes of SHR, immunoassays to tissues of SHR, Wistar Kyoto controls and Sherman strain controls were evaluated. The results demonstrate that the IMCAL content of at least seven SHR tissues is significantly lower than that of the normotensive control strain. Moreover, this change is observed in young 4-week old SHR, prior to development of hypertensive pressure levels.
Because of the long term detrimental effects of essential hypertension, it would be beneficial to have a method for identifying the relative amounts of IMCAL present in the tissues, since decreased amounts of IMCAL are expected to lead to essential hypertension in human subjects as they do in SHR.
Further because of the prevalence of essential hypertension in the human population, it would be beneficial to have a diagnostic method for identifying individuals predisposed to essential hypertension.
Such a method would have far reaching economic importance as a simple and accurate diagnostic test, and would also stimulate that segment of the pharmaceutical market producing drugs for anticipatory treatment of predisposed patients.
Finally, isolation of protein or messenger RNA associated with essential hypertension would allow research into new pharmaceuticals for treatment of essential hypertension.